High molecular weight esthetic compositions

Abstract

Described are high molecular weight glycosaminoglycan (GAG) hydrogel compositions comprising GAGs covalently crosslinked with a carbohydrate crosslinker, and methods of making the high molecular weight GAG hydrogel compositions. Further described are methods of using the high molecular weight glycosaminoglycan (GAG) hydrogel compositions for reparative or plastic surgery, esthetic dermatology, facial contouring, body contouring, and gingival augmentation.

What is claimed: 
     
         1 . A hydrogel product comprising a hyaluronic acid hydrogel crosslinked by amide bonds, obtained by a method comprising:
 crosslinking a hyaluronic acid (HA) having a molecular weight of 2.1 to 10 MDa with a crosslinker, to obtain the hyaluronic acid hydrogel crosslinked by amide bonds, wherein:   the crosslinker is a di- or multinucleophile functional crosslinker comprising a spacer group selected from the group consisting of di-, tri-, tetra-, and oligosaccharides;   the concentration of GAG is between 2% to 10% (w/w); and   the molar ratio of the crosslinker to GAG is less than or equal to 2 mol % per GAG disaccharide.   
     
     
         2 . The hydrogel product according to  claim 1 , wherein the spacer group is trehalose. 
     
     
         3 . The hydrogel product according to  claim 1 , wherein the di- or multinucleophile functional crosslinker is diaminotrehalose (DATH). 
     
     
         4 . The hydrogel product according to  claim 1 , wherein the HA has a molecular weight of 2.1-3.5 MDa. 
     
     
         5 . The hydrogel product according to  claim 1 , wherein:
 the HA has a molecular weight of 2.1-3.5 MDa;   the crosslinker is diaminotrehalose (DATH); and   during the crosslinking, the concentration of HA is between 3-5% (w/w) and the molar ratio of DATH to HA is between 0.9-1.1 mol % per HA disaccharide.   
     
     
         6 . The hydrogel product according to  claim 1 , wherein the hydrogel product is essentially free of synthetic non-carbohydrate structures or linkers. 
     
     
         7 . The hydrogel product according to  claim 1 , wherein the crosslinked HA molecules have an apparent molecular weight (Mwapp) above 1.0 MDa. 
     
     
         8 . The hydrogel product according to  claim 1 , wherein the crosslinked HA molecules have an apparent molecular weight (Mwapp) of 2.1 MDa or above. 
     
     
         9 . The hydrogel product according to  claim 1 , wherein the hydrogel product has a HA concentration of 10-45 mg/mL. 
     
     
         10 . The hydrogel product according to  claim 1 , wherein the crosslinking comprises:
 (1) providing a solution of the HA molecules;   (2) activating carboxyl groups on the HA molecules with a coupling agent to form activated HA molecules;   (3) crosslinking the activated HA molecules via their activated carboxyl groups using a di- or multinucleophile functional crosslinker to obtain a HA hydrogel crosslinked by amide bonds.   
     
     
         11 . The hydrogel product according to  claim 1 , wherein the concentration of the GAG is between 3-5% (w/w) during the crosslinking. 
     
     
         12 . The hydrogel product according to  claim 1 , wherein the molar ratio of crosslinker to HA is between 0.9-1.1 mol % per GAG disaccharide during the crosslinking. 
     
     
         13 . The hydrogel product according to  claim 1 , further comprising a local anesthetic. 
     
     
         14 . The hydrogel product according to  claim 13 , wherein the local anesthetic comprises lidocaine. 
     
     
         15 . A syringe comprising the composition according to  claim 1 . 
     
     
         16 . A method of performing a reparative or esthetic dermatologic treatment, the method comprising:
 injecting a subject with the composition of  claim 1 .   
     
     
         17 . The method of  claim 16 , wherein the injecting is performed as a subdermal, intradermal, subcutaneous, intramuscular, submuscular, or intragingival injection. 
     
     
         18 . The method of  claim 16 , wherein the reparative or esthetic dermatologic treatment comprises dermal filling. 
     
     
         19 . The method of  claim 18 , wherein the injection is administered to fill lines, fine lines, wrinkles, or skin cracks. 
     
     
         20 . The method of  claim 19 , wherein the lines, fine lines, wrinkles, or skin cracks are located on the face, neck, hands, feet, knees, or elbows.